Journal
MOLECULAR AND CELLULAR NEUROSCIENCE
Volume 49, Issue 2, Pages 230-239Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2011.11.006
Keywords
Parkinson's disease; Alpha-synuclein; SNCA; Alternative splicing; Isoform; Substantia nigra
Categories
Funding
- Harvard Brain Tissue Resource Center (PHS
- Belmont, MA) [R24 MH068855]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [NS39793]
- U.S. Department of Defense [W81XWH-05-1-0555]
- Canadian Institutes of Health Research
- Consolidated Anti-Aging Foundation
- Orchard Foundation
- Hansen family
- Harold and Ronna Cooper family
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Alternative splicing is a complex post-transcriptional process that can be regulated by cis-acting elements located within genomic non-coding regions. Recent studies have identified that polymorphic variations in non-coding regions of the alpha-synuclein gene (SNCA) locus are associated with an increased risk for developing Parkinson's disease (PD). The underlying mechanism(s) for this susceptibility may involve changes in alpha-synuclein mRNA expression and alternative splicing. As a first step towards understanding the biology of alpha-synuclein splice variants in PD, we characterized the levels of the full-length SNCA-140 mRNA transcript and SNCA-126, -112, and -98 alternatively spliced variants in different neuronal regions from PD patients or transgenic mice overexpressing human alpha-synuclein (ASO). In human post-mortem tissue, alpha-synuclein spliced transcripts were expressed in a region-specific manner in the cortex, substantia nigra, and cerebellum. We observed increased nigral SNCA-140 and SNCA-126 transcript levels in PD patients when compared to neurologically unaffected cases. Human alpha-synuclein splicing changes were also found to occur in a region-specific manner in ASO mice. Here, SNCA-126, -112, and -98 transcript levels did not increase proportionally with SNCA-140 levels, or parallel the region-specific mouse transcript ratios seen in wild-type (WT) litter-mates. While most transcripts were elevated in ASO mice when compared to WT mice, the most prominent increase was found in the ventral midbrain of 15-month-old ASO mice. These results demonstrate region-specific human alpha-synuclein transcript level abnormalities in PD patients and in a transgenic mouse model of alpha-synucleinopathy. This study is relevant to understanding the normal, adaptive, or pathological role(s) of alpha-synuclein splice variants. (C) 2011 Elsevier Inc. All rights reserved.
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